The Dual Role of Amyloid Beta-Peptide in Oxidative Stress and Inflammation: Unveiling Their Connections in Alzheimer's Disease Etiopathology

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease, and it is currently the seventh leading cause of death worldwide. It is characterized by the extracellular aggregation of the amyloid β-peptide (Aβ) into oligomers and fibrils that cause synaptotoxicity and neuronal death. Aβ exhibits a dual role in promoting oxidative stress and inflammation. This review aims to unravel the intricate connection between these processes and their contribution to AD progression. The review delves into oxidative stress in AD, focusing on the involvement of metals, mitochondrial dysfunction, and biomolecule oxidation. The distinct yet overlapping concept of nitro-oxidative stress is also discussed, detailing the roles of nitric oxide, mitochondrial perturbations, and their cumulative impact on Aβ production and neurotoxicity. Inflammation is examined through astroglia and microglia function, elucidating their response to Aβ and their contribution to oxidative stress within the AD brain. The blood-brain barrier and oligodendrocytes are also considered in the context of AD pathophysiology. We also review current diagnostic methodologies and emerging therapeutic strategies aimed at mitigating oxidative stress and inflammation, thereby offering potential treatments for halting or slowing AD progression. This comprehensive synthesis underscores the pivotal role of Aβ in bridging oxidative stress and inflammation, advancing our understanding of AD and informing future research and treatment paradigms.

Keywords: Alzheimer’s disease; BACE1; amyloid β-peptide; neurodegeneration; nitro-oxidative stress.

Figure 1

Physiological APP cleavage pathways are depicted. The non-amyloidogenic pathway is shown on the left side of the figure. In this pathway, α-secretase cleaves APP, producing sAPPα and CTF83. Subsequently, CTF83 is cleaved by γ-secretase, releasing the P3 peptide extracellularly and AICD intracellularly. The amyloidogenic pathway is shown on the right side of the figure. This pathway involves β-secretase cleavage, which takes place mainly within the intracellular endosome pathway, thus producing sAPPβ and CTF99. CTF99 is then cleaved by γ-secretase at the cell membrane, releasing AICD intracellularly and Aβ extracellularly.

Figure 2

Physiological (A) and pathophysiological (B) brain Aβ equilibrium. (A) Aβ is predominantly produced as Aβ_1-40 and can be degraded within the brain parenchyma or cleared to the blood via LRP, ultimately being degraded in the liver. (B) With age, the production of Aβ_1-42 increases, while its degradation within the brain and clearance decrease. This leads to aggregation, facilitated by protein chaperones and redox-active metals.

Figure 3

NMDAR is a target for Aβ oligomers. (A) LTP allows memory formation by the continuous stimulation of the glutamatergic signaling. Glutamate increases calcium entrance activating nNOS. NO induces the release of glutamate by the presynaptic terminal. Calcium also activates CaMKIIα, that phosphorylates CREB, triggering the transcription of genes needed for synaptic spine growth. (B) Aβ oligomers bind to NMDAR impairing a proper closing, which produces a leak of calcium into the cell that induces synaptotoxicity and neuronal death.

Figure 4

Aβ oligomers produce oxidative stress and neuroinflammation. Synaptic and extrasynaptic Aβ oligomers produce ROS that damage proteins, lipids, and DNA. The Aβ oligomers attract astrocytes that phagocytose them, which triggers their activation, releasing proinflammatory factors and more ROS. Microglia are attracted by chemokines and, after activation, also release proinflammatory factors. All together, these processes produce synaptotoxicity and neurotoxicity.